1. Field of the Invention
This invention relates to an improved process to produce .beta.-(D)2',3'-dideoxyinosine.
2. Background -- Related References
Typically, 2', 3'-dideoxycytidine (ddC) is synthesized from 2'-deoxycytidine.sup.1,2. This is a general method for the synthesis of 2,3'-dideoxynucleosides. The starting materials for this synthesis are, however, extremely expensive and not available in bulk. The reagents required for this deoxygenation, furthermore, are also quite costly.
U.S. Ser. No. 028,817 filed 20 Mar. 1987, owned in common by the assignee of this invention, discloses a process for producing 2', 3'-dideoxynucleosides represented by the formula ##STR1## wherein B is a purine or pyrimidine base and R is H or a hydroxy-protecting group by the steps of (a) converting a .gamma.-carboxy-.gamma.-butyrolactone to a 5-0-hydroxy-protecting group-methyl-.gamma.-butyrolactone, (b) converting the intermediate from step (a) to the 5-0-hydroxy-protecting group-methyl-2',3'-dideoxypentofuranose, (c) converting the intermediate from step (b) to the 1-0-activating group -5-0-hydroxy-protecting group methyl-2', 3'-dideoxypentofuranose, (d) converting the intermediate from step (c) to the 1-leaving group-5-0-hydroxy-protecting group-2', 3'-dideoxypentofuranose, (e) reacting the intermediate from step (d) with an activated purine or pyrimidine base, and (f) recovering the dideoxynucleoside from step (e). The resulting product comprises a mixture of .beta.-and .alpha.-anomers which may be separated using chromatographic and crystallization techniques well-known in the field to which this invention relates.
There remains in the field a need for process improvements whereby the generally active, or more active, .beta.-anomer of (D)-2', 3'-dideoxynucleosides can be selectively obtained without the costly and time-consuming chromatographic or fractional recrystallization separation of .beta.- and .alpha.-anomers. This is particularly important when large quantities of the desired .beta.-anomeric form is desired.
Inosine, chemically 9-.beta.-(D)-ribofuranosylhypoxanthine, biochemically results from enzymatic deamination of adenosine, chemically 9-.beta.-(D)-ribofuranosyl-9H-purin-6-amino. This process, employing adenosine deaminase, acts to metabolically degrade purines to hypoxanthines for excretion in the higher animals. Inosine can be prepared from adenosine by incubation with purified adenosine deaminase obtained from biological sources, e.g. bovine intestine. In applications such as these, where natural substrates are involved, it is known that the enzyme selectively deaminates only one enantiomer of the racemic pair. Enzymatic specificity would not be known beforehand when anomeric mixtures of structurally modified nucleosides were presented as substrates. Specificity on the basis of the known enantiomeric selection process of the enzyme, is not the basis for specificity when applied to an anomeric mixture.